Antibody preparations intended for therapeutic or prophylactic use require stabilizers to prevent loss of activity or structural integrity of the protein due to the effects of denaturation, oxidation or aggregation over a period of time during storage and transportation prior to use. These problems are exacerbated at the high concentrations of antibody often desired for therapeutic administration.
A major aim in the development of antibody formulations is to maintain antibody, solubility, stability and potency of its antigen binding. It is particularly desirable to avoid aggregates and particulates in solution which would require sterile filtration before use for intravenous or subcutaneous injection and limit route of administration. Antibody aggregates can cause pain and anaphylactoid side effects when the formulation containing them is intravenously injected.
Lyophilisation and freeze drying are alternatives to the liquid formulation of antibodies. Both processes have a propensity for inducing denaturation of the antibody and decreasing of its antigen-binding activity particularly upon reconstitution.
Salts, surfactants, pH and tonicity agents such as sugars can contribute to overcoming aggregation problems. Formulation of antibody preparations requires careful selection of these factors among others to avoid denaturation of the protein and loss of antigen-binding activity. Regarding a pH range of an antibody preparation, if an antibody formulation having a low pH value is intravenously injected pain or injection often occurs. Where an antibody formulation is used as an injection, it is desirable to have a pH value in an approximately neutral pH range, it is also advantageous to minimise surfactant levels to avoid bubbles in the formulation which are detrimental for injection into subjects.
A liquid formulation of monoclonal anti-CTLA4 antibody is known from WO2006/096491 (Pharmacia and Upjohn Company), and comprises 20 mg/ml antibody, 20 mM histidine buffer, 84 mg/ml trehelose, 0.2 mg/ml PS80 surfactant, 0.05 mg/ml EDTA pH 5.5.
There is a need for a stable liquid antibody formulation which stably supports high concentrations of bioactive antibody in solution and is suitable for parenteral administration, including intravenous intramuscular, intraperitoneal, intradermal or subcutaneous injection. It is further desirable that the formulation has minimised risk of bubble formation and anaphylactoid side effects.
Furthermore there is a need to provide such a stable liquid formulation for an anti-NGF antibody. NGF is known to play a central role in the development and maintenance of both peripheral and central neurons. In addition to its effects in the nervous system, increased NGF levels has been linked to a variety of inflammatory conditions including systemic lupus erythematosus, multiple sclerosis, psoriasis, arthritis, interstitital cystitis and asthma. NGF also has a demonstrated activity in a variety of pain conditions. It has been shown that the anti-NGF antibody E3 is useful in the treatment of acute and chronic pain conditions including, cancer pain, rheumatoid arthritis pain, osteoarthritis pain and post-surgical pain also (see for example WO2004/058184). There is a need for a stable liquid antibody preparation of an anti-NGF antibody to meet the medical need of patients suffering from inflammatory and pain conditions mediated by NGF.